This project seeks to exploit established mouse PDAC models/alleles, a strong oncogenomics and validation infrastructure, and a comprehensive PDAC genomics database in order to elucidate how signature genetic mutations contribute to the initiation and progression of PDAC and to discover and validate new PDAC oncogenes residing in regions of recurrent focal amplications. This project is driven by the hypothesis that the development of effective targeted therapies demands a comprehensive understanding of how known and novel lesions interact and influence tumor phenotypes. In the context of the established K-Ras-driven PDAC model, Project 1 will examine systematically the role of Ink4a/Arf, p53 and/or Smad4 mutations. All of the projects will work as a cohesive unit to determine the impact of each of these mutations on tumor histopathologic progression, invasive and metastatic potential (this project), angiogenic and stromal response (project 3), signaling pathway activation (project 2), and status of the cancer stem cell compartment (4). The efforts of Project 1 to reconstruct the key genetic events in the mouse will not only, build a PDAC progression model in which genotype-phenotype correlations can be established, but will also establish a modeling foundation upon which roles of yet-to-be discovered PDAC oncogenes can be validated in vivo. Indeed, it has become evident that many PDAC-relevant genes are emerging from ongoing genome scanning and transcriptome profiling efforts. Project 1 will make use of a large high-resolution human PDAC genomic database (including genomic profiles of our mouse tumors) and a battery of established functional and biochemical assays to begin to identify and validate novel PDAC oncogenes. As an illustrative example, Project 1 will pursue a systematic discovery and validation approach to the genes residing within a highly recurrent and focal amplicon with potential relevance to the PI3K pathway. The assays utilized emphasize the target's prevalence on human PDAC samples (in collaboration with the Experimental Pathology and Biobank Cores), its linkage to critical cancer cell signaling pathways (particularly Ras-PI3K in collaboration with Project 2), its expression/activity state in the cancer stem cell compartment (in collaboration with Project 4), and its role in PDAC tumor biology (particularly in shaping/maintaining the tumor microenvironment in collaboration with Project 3). Finally, we develop an inducible system for the P01 in which genotypephenotype of known and yet-to-be-discovered PDAC oncogenes can be elucidated.